In the discussion on different limits to the proliferative lifespan for
different tissues, it was mentioned that lymphocytes may manage only ca.
23 PD in vitro. While some authors from the ageing field have concluded
this, most immunologists working with T cell lines and clones know that
this cannot be the case. Leaving aside mouse T cells for the moment, and
concentrating on less-prone-to-transformation human T cells, simple
arithmetic demonstrates that to obtain a T cell clone in sufficient
numbers to experiment with, more than 23 PD are required. Starting from
one cell, 23 PD represents 4 million cells; commonly (but not always) T
cell clones are obtained which have experienced at least twice this
number of PD. Indeed, many immunologists simply assume that T cell clones
are immortal. In our hands, however, in well over a decade of T cell
cloning, we have not seen a single immortal human line. Average life span
of established clones is estimated at perhaps 40 - 50 PD, with the most
long-lived clones achieving ca. 80 PD (and thus conforming to the
"Weismann-Swim-Hayflick" limit, as Gavrilov & Gavrilova have suggested it
should be designated). There is a great deal of clonal heterogeneity and
many clones survive even less than 23 PD.
How to resolve the discrepancy between a maximum in vitro lifespan of ca.
23 PD established by "T cell gerontologists" and the 80 PD or more
established by "T cell immunologists"? I think that this may have something
to do with the fact that the former have exclusively used uncloned T cell
lines, rather than monoclonal populations. We have observed that uncloned
lines manifest shorter lifespans than monoclonal lines obtained from the
same starting population. Therefore, we believe that this is more to do with
interactions between different T cell clones in the bulk population, where
inhibitory effects predominate after a relatively short time, and that
this has nothing to do with the actual potential lifespan of the cells.
Separating suppressive cells by cloning results in the isolation of
populations with extended lifespan; however, recloning monoclonal
populations does not result in further extension of lifespan beyond the
ca. 80 PD maximum, showing that the cloning procedure per se is not
responsible for extending lifespan.
Although T cells may be a special case, it might be conceivable that
studies on other cell types would show similar discrepancies between the
behaviour of cloned - versus - uncloned populations. Maybe some of the
controversies in the literature on different potential lifespans could be
resolved in this way. Perhaps someone in this discussion group could
comment on that?
Graham Pawelec,
Section for Transplantation Immunology & Immunohematology,
University Hospital,
Tuebingen, Germany
Coordinator, European Union Concerted Action on the Molecular Biology
of Immunosenescence, EUCAMBIS